A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication  

作　　者：Yuzheng Zhou Zongpeng Chen Sijie Liu Sixu Liu Yujie Liao Ashuai Du Zijun Dong Yongxing Zhang Xuan Chen Siyi Tao Xin Wu Aroona Razzaq Gang Xu De-an Tan Shanni Li Youwen Deng Jian Peng Shuyan Dai Xu Deng Xianwen Zhang Taijiao Jiang Zheng Zhang Gong Cheng Jincun Zhao Zanxian Xia 

机构地区：[1]Department of Cell Biology,School of Life Sciences,Central South University,410013 Changsha,China [2]Institute for Hepatology,National Clinical Research Center for Infectious Disease,Shenzhen Third People’s Hospital,The Second Affiliated Hospital,School of Medicine,Southern University of Science and Technology,518112 Shenzhen,China [3]Department of Basic Medicine,School of Medicine,Hunan Normal University,410081 Changsha,China [4]Department of spine surgery,The Third Xiangya Hospital,Central South University,410013 Changsha,China [5]School of Basic Medical Sciences,Anhui Medical University,230032 Hefei,China [6]Hunan Key Laboratory of Neurorestoratology,921 Hospital of Joint Logistics Support Force People’s Liberation Army of China(The Second Affiliated Hospital of Hunan Normal University),410003 Changsha,Hunan,China [7]Department of Geriatric Surgery,Xiangya Hospital,Central South University,410008 Changsha,China [8]Xiangya School of Pharmaceutical Sciences,Central South University,410013 Changsha,China [9]Institute of Infectious Diseases,Shenzhen Bay Laboratory,518132 Shenzhen,China [10]Guangzhou Laboratory,510005 Guangzhou,China [11]Tsinghua University-Peking University Joint Center for Life Sciences,School of Medicine,Tsinghua University,100084 Beijing,China [12]State Key Laboratory of Respiratory Disease,National Clinical Research Center for Respiratory Disease,Guangzhou Institute of Respiratory Health,The First Affiliated Hospital of Guangzhou Medical University,510120 Guangzhou,China [13]Hunan Key Laboratory of Animal Models for Human Diseases,Hunan Key Laboratory of Medical Genetics&Center for Medical Genetics,School of Life Sciences,Central South University,410008 Changsha,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期3112-3129,共18页信号转导与靶向治疗（英文）

基　　金：supported by the National Key Research and Development Program of China(2021YFC2300103);the National Natural Science Foundation of China(U21A20384 and 82072293);the Natural Science Foundation of Hunan Province,China(2022JJ30692);the China Postdoctoral Science Foundation(2023M731520).

摘　　要：The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite its significance,the precise regulatory mechanisms underlying its function remain elusive.In the present study,we unveil that the ORF9b protein of SARS-CoV-2,including emerging mutant strains like Delta and Omicron,can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway,despite certain mutations present among these strains.Moreover,our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70(TOM70)as a substrate receptor,bridging ORF9b with heat shock protein 90 alpha(HSP90α)and Cullin 5(CUL5)to form a complex.Within this complex,CUL5 triggers the ubiquitination and degradation of ORF9b,acting as a host antiviral factor,while HSP90αfunctions to stabilize it.Notably,treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b,leading to a pronounced inhibition of SARS-CoV-2 replication.Single-cell sequencing data revealed an up-regulation of HSP90αin lung epithelial cells from COVID-19 patients,suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90αto evade the host immunity.Our study identifies the CUL5-TOM70-HSP90αcomplex as a critical regulator of ORF9b protein stability,shedding light on the intricate host–virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.

关 键 词：STABILITY MODULATOR offering 

分 类 号：R373.1[医药卫生—病原生物学]